Microbiome and Human Health

The Human Microbiome and Human Health

While the typical human body contains an estimated 10 trillion human cells, it also contains over 100 trillion bacteria and other microbes. The complex mutually beneficial symbiotic relationship (def) between humans and their natural microbes is critical to good health. It is now recognized that the millions of genes associated with the normal flora or microbiota (def) of the human body -especially in the intestinal tract - aid in the digestion of many foods, the regulation of multiple host metabolic pathways, and the regulation the body's immune defenses. These collective microbial genes are referred to as the human microbiome (def). There are currantly an estimated 3, 000,000 - 5,000,000 genes from over 1000 species that constitute the human microbiome compared to the 20,000 - 25,000 genes that make up the human genome.

Regulation of Host Metabolism

The mutually beneficial interaction between the human host and its resident microbiota is essential to human health. Microbial genes produce metabolites essential to the host while human genes contribute to development of the microbiota. The microbiome aids in the digestion of many foods, especially plant polysaccharides that would normally be undigestible by humans, and the regulation of many host metabolic pathways. The metabolism of many substrates in the human body is carried out by a combination of genes from both the microbiome and the human genome. Within the intestinal tract there is constant chemical communication not only between microbial species but also between microbial cells and human cells. Multiple factors, including diet, antibiotic use, disease, life style, and a person's environment can alter the composition of the microbiota within the gastrointestinal tract and, as a result, influence host biochemistry and the body's susceptibility to disease. Metabolic disorders such as diabetes, nonalcoholic fatty liver disease, hypertension, obesity, gastric ulcers, colon cancer, and possibly some mood and behavior changes through hormone signaling have been linked to alterations in the microbiota.

Regulation of Immunity

There is ever growing evidence that commensal bacteria (def) of the gastrointestinal tract, as well as parasitic gastrointestinal helminths, may have coevolved with the human body over the past 200,000 year in such a way that genes from the human microbiota may play a significant role in regulating the human immune responses by providing a series of checks and balances that prevent the immune system from being too aggressive and causing an autoimmune attack upon the body's own cells, while still remaining aggressive enough to recognize and remove harmful pathogens. The microbiota affects the development of the immune system while the immune system influences the composition of the microbiota.

As exposure to and colonization with these once common human organisms has drastically changed over time as a result of less exposure to mud, animal and human feces,and helminth ova, coupled with ever increasing antibiotic use that destroys normal flora, improved sanitation, changes in the human diet, increased rate of cesarean sections,decreased rate of breastfeeding, and improved methods of processing and preserving of food, the rates of allergies, allergic asthma, and autoimmune diseases (inflammatory bowel disease, Crone's disease, irritable bowel syndrome, type-1 and type-2 diabetes, and multiple sclerosis for example) have dramatically increased in developed countries while remaining relatively low in undeveloped and more agrarian parts of the world.

Numerous experiments in germ-free mice (mice with no intestinal commensals) have shown them to be much more susceptible to allergic asthma and autoimmune diseases such as colitis then normal mice. Feeding commensals or nematode ova to newborn germ-free mice, in turn, reduces the occurrence to these disorders. An imbalance in the relationship between proinflammatory T_H17 cells and inflammation-suppressing T_reg cells (to be discussed under adaptive immunity in Unit 5) appears to increase the risk of inflammatory autoimmune diseases, while an imbalance between T_H1 and T_H2 cells seems to contribute to the risk of allergies and asthma. For example, a common commensal colon bacterium Bacteroides fragilis produces a molecule called polysaccharide A that dendritic cells engulf, process and present to naive T4-lymphocytes. This interaction stimulates the differentiation of the naive T4-lymphocytes into anti-inflammatory T_reg cells that suppress the activity of proinflammatory T_H17 cells. Without colonization with B. fragilis, the proinflammatory T_H17 cells are not suppressed and there is an increased risk of inflammatory autoimmune diseases.

Normal intestinal microbiota also appear to regulate the intestinal levels of the invarient natural killer (iNKT) cells (to be discussed under innate immune responses in Unit 4). iNKT cells recognize endogenous and exogenous lipid antigens presented on CD1d molecules by dendritic cells and in response, secrete proinflammatory cytokines. Germ free mice show an accumulation of iNKT cells in the colon and in the lungs and have an increased risk of intestinal bowel disease and allergic asthma. Neonatal germ free mice that were subsequently colonized with normal microbiota were protected from this iNKT cell accumulation and the resulting inflammatory pathology. It has been proposed that microbes the human body has been traditionally exposed to from early childhood throughout most of human history might play a role in developing normal iNKT cell numbers and iNKT cell responses.